Method of determining an analyte concentration

ABSTRACT

A method of determining an analyte concentration in a sample by a sensor is disclosed. The method comprises analyzing a sample signal generated by the sensor for an analyte being measured. If the sample signal is normal, the method comprises comparing the sample signal with a first reference signal of a reference solution measured prior to measuring the sample in order to determine the analyte concentration. If the sample signal is abnormal, the method comprises comparing the sample signal with a calculated reference signal point obtained by interpolation between the first reference signal and a second reference signal of the same reference solution measured after measuring the sample. Various methods of determining and handling errors based on signal patterns are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to European Patent Application No.17159681.0, filed 7 Mar. 2017, the disclosure of which is herebyincorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure relates to a more accurate method of measuring ananalyte concentration in a sample by a sensor.

BACKGROUND

In medicine, a doctor's diagnosis and patient treatment often relies onthe measurement of the concentration of analytes or other parameters ina patient sample. This measurement is typically carried out by in-vitrodiagnostic instruments that can be configured to analyze certain typesof samples and detect certain types of analytes using various detectingtechnologies. As the life of patients may depend on the precision andthe reliability of such measurements it is important that theinstruments perform correctly.

It is a general requirement for in-vitro diagnostic systems to implementa set of Quality Control (QC) procedures to check that the instrumentsare working correctly.

One of these procedures is calibration. In most cases calibration isperformed using standard solutions, with known concentrations. In thisway it is possible to correlate a measured signal to a quantitativeresult. Calibration should be performed more or less frequentlydepending on the system and other variable factors that may affectperformance.

In addition, between consecutive calibrations, one or more referencesamples, also called QC samples, with known values of the analytes orparameters of interest are typically also measured, in the same way astest samples are measured, in order to further check that the calibratedinstrument is actually within the specifications or admissible range.

However, even after correct calibration and validation with QC samples,detectors and sensors used to measure analyte concentrations can besubject to interferences, e.g., due to presence and/or highconcentration of interfering substances in a particular test sample, andcan be subject to temporary signal instability. In particular, somesensors may experience a signal drift that in some cases may remainunnoticed. This can lead to measurement errors.

Also, it is possible that signal drift occurs during calibration ormeasurement of QC samples.

In most cases an error occurred during calibration or a quality controlis reported as a calibration failure or as a QC failure. Even in suchcases, however, it is not always clear what the cause of the failure is.The failure may be due to a malfunctioning sensor but could be also dueto other malfunctioning parts or interferences within the instrument,e.g., presence of air bubbles, clogging, contamination or mechanicalfailures.

If the cause cannot be determined, this may lead to wrong assumptionsand false decisions when trying to resolve the issue. For example, auser may decide to replace a sensor whereas the cause of the error is tobe found in another part of the instrument, thus resulting in increasedcosts and instrument down times.

SUMMARY

It is against the above background that the present disclosure providescertain unobvious advantages and advancements over the prior art. Inparticular, the inventors have recognized a need for improvements inmethods for determining an analyte concentration.

Although the embodiments of the present disclosure are not limited tospecific advantages or functionality, it is noted that the presentdisclosure provides a new method that enables to greatly reducemeasurement errors. This is achieved by analyzing the sample signal and,based on the signal pattern, applying corrective measures, thereforeincreasing accuracy and reliability in determining concentrations ofanalytes in a sample. The present disclosure further enables todiscriminate sensor errors from other types of errors and to triggeradditional actions that facilitate troubleshooting, reduce maintenanceand service costs, accelerate complaint handling and minimize instrumentdown times.

In accordance with one embodiment of the present disclosure, a method ofdetermining an analyte concentration in a sample by a sensor isprovided, the method comprising analyzing a sample signal for an analytebeing measured and if the sample signal is normal, that is if it remainswithin an expected or predefined range and/or if it follows an expectedtrend over a predefined measurement time, the method comprises comparingthe sample signal with a first reference signal of a reference solutionmeasured prior to measuring the sample in order to determine the analyteconcentration, and if the sample signal is abnormal, that is if it fallsat least in part out of the expected or pre-defined range and/or if itdrifts beyond a predefined threshold over a predefined measurement time,the method comprises comparing the sample signal with a calculatedreference signal point obtained by interpolation between the firstreference signal and a second reference signal of the same referencesolution measured after measuring the sample.

These and other features and advantages of the embodiments of thepresent disclosure will be more fully understood from the followingdetailed description taken together with the accompanying claims. It isnoted that the scope of the claims is defined by the recitations thereinand not by the specific discussions of features and advantages set forthin the present description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the embodiments of the presentdisclosure can be best understood when read in conjunction with thefollowing drawings, where like structure is indicated with likereference numerals and in which:

FIG. 1 shows an example of an analytical instrument and sensor comprisedtherein in accordance with an embodiment of the present disclosure;

FIG. 2 generally depicts a method of determining an analyteconcentration in a sample by a sensor in accordance with an embodimentof the present disclosure;

FIG. 3 schematically shows three examples of sample signal in accordancewith an embodiment of the present disclosure;

FIG. 4 depicts a method of determining an analyte concentration when thesample signal is normal in accordance with an embodiment of the presentdisclosure;

FIG. 5 depicts a method of determining an analyte concentration when thesample signal is abnormal in accordance with an embodiment of thepresent disclosure;

FIG. 6 depicts a method of determining an error in accordance with anembodiment of the present disclosure;

FIG. 7 depicts another method of determining an error in accordance withan embodiment of the present disclosure;

FIG. 8 depicts another method of determining an error in accordance withan embodiment of the present disclosure; and

FIG. 9 depicts a method of handling signals and errors in accordancewith an embodiment of the present disclosure.

Skilled artisans appreciate that elements in the figures are illustratedfor simplicity and clarity and have not necessarily been drawn to scale.For example, dimensions of some of the elements in the figures may beexaggerated relative to other elements to help improve understanding ofthe embodiment(s) of the present disclosure.

DETAILED DESCRIPTION

A method of determining an analyte concentration in a sample by a sensoris disclosed. The method comprises analyzing a sample signal generatedby the sensor for an analyte being measured. If the sample signal isnormal, the method comprises comparing the sample signal with a firstreference signal of a reference solution measured prior to measuring thesample in order to determine the analyte concentration. If the samplesignal is abnormal, the method comprises comparing the sample signalwith a calculated reference signal point obtained by interpolationbetween the first reference signal and a second reference signal of thesame reference solution measured after measuring the sample.

The term “sample” is herein generally used to indicate either a testsample or a QC sample or a calibrator.

The term “test sample” refers to a biological material suspected ofcontaining one or more analytes of interest and whose detection,qualitative and/or quantitative, may be associated to a clinicalcondition. The test sample can be derived from any biological source,such as a physiological fluid, including blood, saliva, ocular lensfluid, cerebral spinal fluid, sweat, urine, milk, ascites fluid, mucous,synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells or thelike. The test sample can be pretreated prior to use, such as preparingplasma from blood, diluting viscous fluids, lysis or the like; methodsof treatment can involve filtration, centrifugation, distillation,concentration, inactivation of interfering components, and the additionof reagents. A test sample may be used directly as obtained from thesource in some cases or following a pretreatment and/or samplepreparation workflow to modify the character of the sample, e.g., afteradding an internal standard, after being diluted with another solutionor after having being mixed with reagents, e.g., to enable carrying outone or more in vitro diagnostic tests, or for enriching(extracting/separating/concentrating) analytes of interest and/or forremoving matrix components potentially interfering with the detection ofthe analyte(s) of interest.

According to an embodiment, the test sample is blood or a bloodderivative such as plasma or serum. According to certain embodiments,analytes of interest are gases, such as O₂ and CO₂, blood electrolytessuch as Sodium (Na⁺), Potassium (K⁺), Chloride (Cl⁻), Calcium (Ca⁺⁺),protons (H⁺) in relation to pH, metabolites such as Glucose and Lactate,drugs of abuse, therapeutic drugs, hormones, markers, proteins and thelike. Other analytes of interest are hemoglobin, hemoglobin derivativessuch as Deoxygenated hemoglobin, Oxyhemoglobin, Carboxyhemoglobin,Methemoglobin, and bilirubin. According to an embodiment a parameter ofinterest is hematocrit. The list is however not exhaustive.

The term “QC sample” refers to a reference sample, that mimics a testsample, and that contains known values of one or more QC substances.Typically, QC samples are supplied in one or more levels, e.g., two orthree levels that correspond to different concentration ranges of the QCsubstances. QC samples are typically measured in the same way and underthe same conditions as test samples are measured, in order to check thata calibrated sensor is actually within the specifications or admissiblerange.

A “QC substance” can be an analyte identical to an analyte of interest,the concentration of which is known, or that generates by reaction ananalyte identical to an analyte of interest, the concentration of whichis known, e.g., CO₂ from bicarbonate, or it can be any other equivalentsubstance of known concentration, which mimics the analyte of interestor that can be otherwise correlated to a certain parameter of interest,e.g., a dye that behaves optically similar to hemoglobin or bilirubin.

A “calibrator” is a calibration solution that contains known values ofone or more calibration materials used for calibration and that ismeasured under the same conditions as a sample. In particular, acalibrator can be measured like a test sample or a QC sample between afirst reference solution measurement and a second reference solutionmeasurement. Typically, one or two calibrators are used for a one-pointor two-point calibration respectively, when the sensor responds linearlyto analyte concentrations. Three or more calibrators may be used if thecalibration curve is non-linear. In particular, also calibrators can beprovided in different levels that correspond to different concentrationranges of the QC materials.

A calibration material can be the same as a QC substance.

A “reference solution” is a standard solution such as a calibrator, withknown analyte concentration, that may be used for calibration, and thatis routinely used for obtaining a reference measurement before and aftera sample measurement.

According to an embodiment the reference solution is a standby solution.A “standby solution” is a solution that is used to rinse the sensorafter a sample measurement and is kept in contact with the sensor untilit is replaced by another sample.

The term “sensor” is herein generically used to indicate a detectorconfigured to respond to changes of analyte concentration in a sampleand generate a correlated signal output that can be quantified anddigitized. The sensor can be a biosensor, a chemical sensor or aphysical sensor. Also, the sensor can be selective or even specific withrespect to one analyte of interest in a sample or can be configured todetect and quantify a plurality of different analytes of interest.

The sensor is typically part of a larger in-vitro diagnostic system. An“in-vitro diagnostic system” is a laboratory automated or semi-automatedsystem dedicated to the analysis of samples for in vitro diagnostics.The in-vitro diagnostic system may have different configurationsaccording to the need and/or according to the desired laboratoryworkflow. The in-vitro diagnostic system can comprise one or moreanalytical instruments, comprising at least one detector or sensor,designed to execute respective workflows that are optimized for one ormore certain types of analysis, and to detect certain types ofparameters, e.g., gases, electrolytes, metabolites, clinical chemistryanalytes, immunochemistry analytes, coagulation parameters, hematologyparameters, etc. Thus the in-vitro diagnostic system may comprise oneanalytical instrument or a combination of any of such analyticalinstruments with respective workflows and respective detectors, wherepre-analytical and/or post analytical modules may be coupled toindividual analytical instruments or be shared by a plurality ofanalytical instruments. In alternative pre-analytical and/orpost-analytical functions may be performed by units integrated in ananalytical instrument. The in-vitro diagnostic system can comprisefunctional units such as liquid handling units for pipetting and/orpumping and/or mixing of samples and/or reagents and/or system fluids,and also functional units for sorting, storing, transporting,identifying, separating, detecting.

According to an embodiment the in-vitro diagnostic system comprises ananalytical instrument with at least one sensor.

According to an embodiment, the sensor may comprise a plurality ofsensor zones, e.g., arranged in a flow-through sensoric path, eachsensor zone being configured to be specific or selective with respect toone analyte of interest.

According to an embodiment, the sensor is configured for detecting andquantifying any one or more of a gas, an electrolyte, a metabolite.

According to certain embodiments, the sensor is based on thepotentiometric, amperometric, conductometric, or optical measurementprinciple.

According to an embodiment, the sensor is an ion-selective electrode(ISE) sensor and the sample signal is a potentiometric signal.

According to an embodiment, the analyte is any of a proton, chlorideion, sodium ion, potassium ion, calcium ion.

According to certain embodiments the sensor is a pH sensor or an ISEsensor for determining electrolyte values such as Na⁺, K⁺, Ca²⁺ and Cl⁻.

A pH sensor typically comprises a pH-sensitive membrane. Depending onthe pH value of the test sample, electric potential is generated at theboundary layer between the membrane and the sample. This potential canbe measured potentiometrically by a reference sensor.

Also Na⁺, K⁺, Ca²⁺ and Cl⁻ ISE sensors typically work according to thepotentiometric measuring principle. They differ only by differentmembrane materials that enable sensitivity for the respectiveelectrolytes.

A “sample signal” is the signal output generated by the sensor whenmeasuring an analyte concentration in a test sample, QC sample orcalibrator.

A “reference signal” is the signal output generated by the sensor whenmeasuring a reference solution and in particular an analyteconcentration in the reference solution before and/or after measuring asample.

A signal may be a continuous signal over a period of time or it mayrefer to a single measurement point or a plurality of discretemeasurement points over time, to form a signal pattern.

A “signal pattern” refers to the signal behavior over time either withrespect to a continuous signal or to a plurality of measurement pointsover time.

A signal or signal pattern, i.e., either a sample signal or referencesignal, is “normal” if the signal remains within an expected orpredefined range and/or if it follows an expected trend over a limitedmeasurement time.

A signal or signal pattern, i.e., either a sample signal or referencesignal, is “abnormal” whenever it deviates from normal behavior and inparticular if it falls at least in part out of the expected orpre-defined range and/or if it shows a significant signal drift, i.e.,if the signal drifts beyond a predefined threshold, over a limitedmeasurement time.

The limited measurement time can be any predefined time, but typicallyless than a minute, e.g., about 30 seconds.

According to an embodiment, a signal or signal pattern, i.e., either asample signal or reference signal, is normal if the normalizedmeasurement points of the signal are of the same sign and it is abnormalif the normalized measurement points of the signal have at least in partopposite sign.

If the sample signal is normal, the method comprises comparing thesample signal with a first reference signal of a reference solutionmeasured prior to measuring the sample in order to determine the analyteconcentration. More specifically, the method comprises comparing atleast one measurement point of the sample signal with at least onemeasurement point of a first reference signal of a reference solutionmeasured prior to measuring the sample. This corresponds to one-pointcalibration with the reference solution being measured before measuringthe sample in order to generate a first reference signal and calculatethe analyte concentration in the sample.

According to an embodiment, the first reference signal is the lastavailable measurement point or a projected (extrapolated) measurementpoint of the measured reference solution. The at least one measurementpoint of the first reference signal may be however another measurementpoint such as one of the last few measurement points, a minimum point ora maximum point or an average of a plurality of measurement pointsmeasured over time.

If the sample signal is abnormal, the method comprises comparing thesample signal with a calculated reference signal point obtained byinterpolation between the first reference signal and a second referencesignal of the same reference solution measured after measuring thesample. More specifically, the method comprises comparing at least onemeasurement point of the sample signal with a calculated referencesignal point obtained by interpolation between the at least onemeasurement point of the first reference signal and at least onemeasurement point of a second reference signal of the same referencesolution measured after measuring the sample. This means measuring thesame reference solution before and after measuring the sample in orderto generate a first reference signal and a second reference signalrespectively, both of which are taken into account for calculating theanalyte concentration. This is because the second reference signal canbe different from the first reference signal, especially if a signaldrift occurs during sample measurement, and taking only the firstreference signal or only the second reference signal into account isless accurate. This corresponds to one-point calibration, however withrespect to a calculated (interpolated) reference value by measuring thesame reference solution before and after measuring a sample.

It can be advantageous to use a standby solution as the referencesolution to be measured before and after sample measurement as thestandby solution can be used to rinse the sensor and contact the sensorbetween different samples and its signal can be therefore detected inproximity of each sample measurement, including before and after eachsample measurement.

According to one embodiment the at least one measurement point of thesecond reference signal is the first available measurement point of thesecond reference signal. The at least one measurement point of thesecond reference signal may be however another measurement point such asone of the first few measurement points, a minimum point or a maximumpoint or an average of a plurality of measurement points.

According to one embodiment the at least one measurement point of thesample signal is the last available measurement point of the samplesignal or a projected (extrapolated) point of the sample signal. The atleast one measurement point of the sample signal may be however anothermeasurement point such as one of the last few measurement points, aminimum point or a maximum point or an average of a plurality ofmeasurement points.

According to one embodiment, if the sample signal is abnormal, themethod comprises flagging the sample measurement and/or indicating thatthe analyte concentration is an interpolated analyte concentration.

According to one embodiment, if the sample signal is repeatedly abnormalfor consecutive sample measurements, e.g., for a predetermined number oftimes, where the sample can be the same sample or different samples, themethod comprises indicating a sensor error.

According to one embodiment where the sample is a QC sample and thesample signal, the first reference signal and the second referencesignal are normal and a QC failure occurs, the method comprisesrepeating measurement of the QC sample and/or indicating an error otherthan a sensor error.

According to one embodiment where the sample is a QC sample and any oneor more of the sample signal, the first reference signal and the secondreference signal are abnormal and a QC failure occurs a pre-definednumber of times, the method comprises indicating a sensor error. Themethod may include attempting to resolve the cause of the sensor errorbefore indicating a sensor error.

According to one embodiment where the sample is a calibrator and thesample signal, the first reference signal and the second referencesignal are normal and a calibration failure occurs, the method comprisesrepeating measurement of the calibrator and/or indicating an error otherthan a sensor error.

According to one embodiment where the sample is a calibrator and whereany one or more of the sample signal, the first reference signal and thesecond reference signal are abnormal and a calibration failure occurs apre-defined number of times, the method comprises indicating a sensorerror. The method may include attempting to resolve the cause of thesensor error before indicating a sensor error.

According to one embodiment, the method comprises saving, at leasttemporarily, any signal and/or any error in a database and/or troubleshooting report of an analytical instrument.

According to one embodiment, the method comprises transmitting andcollecting any signal and/or any error from one or more local analyticalinstruments to a remote server or cloud for monitoring instrument and/orsensor performance, and/or for analyzing data to improve instrumentand/or sensor performance and/or for facilitating service or troubleshooting and/or for remotely triggering corrective actions or othertypes of actions.

Other and further objects, features and advantages will appear from thefollowing description of exemplary embodiments and accompanyingdrawings, which serve to explain the principles more in detail.

FIG. 1 shows schematically an example of an analytical instrument 100.The analytical instrument 100 comprises a first detector 40 and a seconddetector 50 for detecting respective parameters of a test sample 1.

The first detector 40 comprises an optical unit 41 and in particular anoximetry unit for photometrically detecting any one or more ofhemoglobin, including derivatives of hemoglobin, and bilirubin. Inparticular, the optical or oximetry unit 41 comprises a light source 42,an optical sensor 43 such as a photodiode array, a sample cuvette 44arranged between the light source 42 and the optical sensor 43 andoptical elements such as lenses and a polychromator (not shown), forguiding light from the light source 42 to a test sample 1 in the cuvette44 and from the test sample 1 to the optical sensor 43 for measuring anabsorbance spectrum.

The second detector 50 is embodied as a plug-in cartridge comprising aflow-through sensoric path 51, comprising a gas sensoric zone 52comprising a PO2 sensor, a PCO2 sensor and a pH sensor, a metabolitesensoric zone 53, comprising a glucose sensor and a lactate sensor, andan electrolyte sensoric zone 54, comprising ISE sensors for detectingrespectively Na⁺, K⁺, Ca²⁺, and Cl⁻.

The analytical instrument 100 further comprises fluidic lines 60, afluid injector 61, valves 62 and pumps 63 for moving fluids through thefluidic lines 60 and in particular in and out of the cuvette 44 of thefirst detector 40 and/or through the sensoric path 51 of the seconddetector 50, where respective analytes can be determined.

The analytical instrument 100 further comprises a fluid package 70comprising fluid reservoirs, including a reference solution (REF), afirst calibrator (Cal 1), a second calibrator (Cal 2), a standbysolution (STDBY), a wetting fluid (WET) and two waste containers (W).The wetting fluid (WET) is used every time a new cartridge or detector50 is plugged for conditioning the new cartridge 50.

The Na⁺, K⁺, Ca²⁺, Cl⁻, pH and CO2 parameters are calibrated using theSTDBY and Cal 2 solutions, which contain a defined quantity ofelectrolytes and acidic or alkaline components of a pH buffer system. Byensuring airtight access to the calibration solutions, the CO2 contentcan be kept steady and then used as a basis for calibration.

The CAL 2 solution contains a very low concentration of oxygen and thusis used to calibrate the low calibration point in a two-pointcalibration. The high calibration point is calibrated using the standbysolution. The oxygen concentration of the standby solution correspondsto that of the ambient air.

For the glucose/lactate sensors, due to the non-linear nature of thecalibration curve, three calibration points are determined. The STDBY,Cal 1 and Cal 2 solutions are used for this purpose.

Calibrating the oximetry unit 41 requires wavelength calibration of thepolychromator and layer thickness calibration of the cuvette 44. Forthis purpose, the optical unit 41 comprises a second light source (notshown), which is a neon lamp. The neon lamp is a gas discharge light,which emits only certain defined wavelengths. The peaks in the neonemission spectrum are used to calibrate the wavelength scale. The layerthickness of the cuvette 44 is calibrated using the Cal 2 solution,which contains a dye for this purpose.

The standby solution STDBY is also used for rinsing the fluidic lines60, the flow-through path 51 and the cuvette 44.

The analytical instrument 100 further comprises QC samples 30, suppliedin three levels of respective concentration ranges for each parameter.In particular, the QC samples 30 comprise QC substances in differentconcentrations for different levels, which are required for performingthe QC procedure with respect to both the first detector 40 and thesecond detector 50.

The analytical instrument 100 further comprises a controller 80configured to determine an analyte concentration, e.g., in a test sample1 or QC sample 30 or calibrator, e.g., Cal 2. In particular, thecontroller 80 is configured to analyze a sample signal generated, e.g.,by any of the sensors in the second detector 50, e.g., any of the ISEsensors of the electrolyte sensoric zone 54, for a respective analytebeing measured, and judging if the sample signal is normal or abnormal.If the sample signal is normal, the controller 80 is configured tocompare the sample signal with a first reference signal obtained bymeasuring the standby solution STDBY as reference solution prior tomeasuring the sample 1, 30 in order to determine the analyteconcentration. If the sample signal is abnormal, the controller 80 isconfigured to compare the sample signal with a calculated referencesignal point obtained by interpolation between the first referencesignal and a second reference signal of the same standby solution STDBYmeasured after measuring the sample 1, 30 or Cal 2.

In the flow diagram of FIG. 2, a method of determining an analyteconcentration in a sample by a sensor is illustrated. The methodcomprises measuring a sample and analyzing the sample signal for ananalyte being measured. If the sample signal is normal, the methodcomprises comparing the sample signal with a first reference signal of areference solution measured prior to measuring the sample, thusperforming a calibration based on such first reference signal, in orderto determine the analyte concentration. If the sample signal isabnormal, the method comprises calculating a reference signal point byinterpolation between the first reference signal and a second referencesignal of the same reference solution measured after measuring thesample, and comparing the sample signal with the calculated referencesignal point, thus performing a calibration based on such calculatedreference signal point, in order to determine the analyte concentration.

FIG. 3 schematically shows three examples of normalized sample signalsgenerated by an ISE sensor, although other types of sample signal arealso possible and may be different for different types of sensor. Thesample signals are measured in electrical potential (mV) versus time inseconds (s). The first sample signal on the top of FIG. 3 has a typicalpattern where the electrical potential keeps decreasing over time untilstabilizing. This is an example of normal sample signal or signalpattern N. With respect to the second sample signal in FIG. 3, theelectrical potential tends to slowly increase again after decreasing,however still remaining negative over the measurement time, i.e., thenormalized measurement points of the sample signal are of the same sign.This sample signal can be considered still in an acceptable normal rangeN′. With respect to the third sample signal at the bottom of FIG. 3, aclear signal drift can be observed. In particular, the electricalpotential decreases in a first phase before significantly increasingagain and passing from negative to positive sign, i.e., the normalizedmeasurement points have in part opposite sign. In this case the samplesignal is abnormal A.

FIG. 4 shows in more detail a method of determining an analyteconcentration when the sample signal is normal N. In the graph of FIG.4, where electrical potential in mV is plotted versus time in seconds(s), a sample signal N between a first reference signal Ref1 and asecond reference signal Ref2 are shown. The sample signal N is generatedduring a measurement time window t3. The first reference signal Ref1 andthe second reference signal Ref2 are generated by measuring the samereference solution before and after measuring the sample in a timewindow t1 and t5 respectively. The time window t2 between t1 and t3 isthe time during which the reference solution is removed from the sensorand it is replaced by the sample. The time window t4 between t3 and t5is the time during which the sample is removed from the sensor and it isreplaced by the reference solution. Advantageously the referencesolution is the same standby solution SDTBY that is used also to rinsethe sensor and is kept in contact with the sensor until a sample isintroduced.

In this case, where the sample signal is normal N, the method comprisescomparing the sample signal N with the first reference signal Ref1 inorder to determine the analyte concentration. In particular, ameasurement point P3 or a projected point P3′ of the sample signal N,and a measurement point P1 or a projected point P1′ of the firstreference signal Ref1 respectively may be chosen when comparing thesample signal N with the first reference signal Ref1. In this example,P3 is the last available measurement point of the sample signal N and P1is the last available measurement point of the first reference signalRef1. The difference Δ1 between P3 and P1 or the difference Δ1′ betweenP3′ and P1′ may be used to determine the analyte concentration in thesample, where Δ1 and Δ1′ provide comparable results. The secondreference signal Ref2 is not taken into account. It is noted thatwhereas the sample signal is normal N, and despite the same referencesolution is measured before and after measuring the sample the secondreference signal Ref2 can be different from the first reference signalRef1 or offset with respect to the first reference signal Ref1.

FIG. 5 shows in more detail a method of determining an analyteconcentration when the sample signal is abnormal A. Analogously to FIG.4, the sample signal A is shown between a first reference signal Ref1and a second reference signal Ref2, where also in this case Ref1 andRef2 are obtained by measuring the same reference solution, and inparticular the same standby solution SDTBY before and after measuringthe sample. The time windows t1-t5 are the same as for FIG. 4. However,in this case, where the sample signal is abnormal A, the secondreference signal Ref2 is taken into account. In particular, the methodcomprises comparing the sample signal with a calculated reference signalpoint I1, I1′ obtained by interpolation between the first referencesignal Ref1 and the second reference signal Ref2.

In this example a projected point P1′, P1″ of the first reference signalRef1 and a measurement point P2 of the second reference signal Ref2respectively are chosen for obtaining a calculated reference signalpoint I1, I1′ in correspondence to a measurement point P3 or projectedmeasurement point P3′ of the sample signal A. In this example, P3 is thelast available measurement point of the sample signal A, P2 is the firstmeasurement point of the second reference signal Ref2, P1′ is aprojected point of the first reference signal Ref1 in correspondence tothe first measurement point of the sample signal A and P1″ is aprojected point of the first reference signal Ref1 in correspondence tothe measurement point with minimum value of the sample signal A. Thedifference Δ2 between P3 and I1 or the difference Δ2′ between P3′ andI1′ may be used to determine the analyte concentration in the sample,where Δ2 and Δ2′ provide comparable results.

It is noted that both the sample signal pattern A and the secondreference signal Ref2 have an abnormal pattern meaning that an error mayhave occurred already during sample measurement. In this case using boththe first reference signal Ref1 and the second reference signal Ref2contributes to compensate for any eventual error and to determine a moreaccurate analyte concentration.

FIG. 6 depicts a method of determining an error. In particular, if thesample signal pattern is repeatedly abnormal for consecutive samplemeasurements, i.e., for more than a pre-defined number of times n, wheren can be any number including 1, the method comprises indicating asensor error.

FIG. 7 depicts another method of determining an error. In particular, ifthe sample is a QC sample and a QC failure occurs despite the signalpatterns, including the sample signal pattern and the reference signalpatterns, are normal, the method comprises repeating measurement of theQC sample and/or indicating an error other than a sensor error. Inparticular, the error other than a sensor error may be indicated aftermeasurement of the QC sample n times, where n can be any numberincluding 1, and obtaining a QC failure despite normal signal patterns.On the other hand, if a QC failure occurs and in addition any one ormore of the signal patterns, including the sample signal pattern and thereference signal patterns, are abnormal the method comprises indicatinga sensor error, after eventually attempting to resolve the cause of theerror. In particular, the sensor error may be indicated aftermeasurement of the QC sample n times, where n can be any numberincluding 1, and after failing to fix the error.

FIG. 8 depicts another method of determining an error. In particular, ifthe sample is a calibrator, e.g., CAL 2, and a calibration failureoccurs despite the signal patterns, including the sample signal patternand the reference signal patterns are normal, the method comprisesrepeating measurement of the calibrator and/or indicating an error otherthan a sensor error. In particular, the error other than a sensor errormay be indicated after measurement of the calibrator n times, where ncan be any number including 1, and obtaining a calibration failuredespite normal signal patterns. On the other hand, if a calibrationfailure occurs and in addition any one or more of the signal patterns,including the sample signal pattern and the reference signal patterns,are judged to be abnormal the method comprises indicating a sensorerror, after eventually attempting to resolve the cause of the error. Inparticular, the sensor error may be indicated after measurement of thecalibrator n times, where n can be any number including 1, and afterfailing to fix the error.

FIG. 9 depicts a method of handling signals and errors among otherpossible data. The method comprises saving, at least temporarily, signalpatterns and/or any error in a database and/or trouble shooting report90, 90′ of an analytical instrument 100, 100′.

The method comprises transmitting and collecting any signal and/or anyerror from one or more local analytical instruments 100, 100′ to aremote server or cloud 200 for monitoring instrument and/or sensorperformance, and/or for analyzing data to improve instrument and/orsensor performance and/or for facilitating service or trouble shootingand/or for remotely triggering corrective actions or other types ofactions. Actions may be triggered also locally at instrument level viacommunication between the database 90, 90′ and the controller 80, 80′.

The remotely collected data may be used for example for updating themethod (algorithm) of determining analyte concentration, e.g., byadapting the range or threshold that defines when a signal is normal orabnormal, or the requirements for indicating a sensor error, e.g., bychanging the number of times a QC failure and/or a calibration failureand/or an abnormal signal has to occur before indicating an error and/orfor updating or adding procedures for resolving causes of errors.

The collected data may be also used for proactive customer service,e.g., to inform a user and provide a new sensor when a sensor error isrecognized and/or automatically schedule a field service when anothermalfunctioning requiring a field service engineer is recognized.

Also, based on a user behavior, e.g., usage/measurement frequency, it ispossible to automatically reserve an adequate amount of sensors for eachuser, or suggest a more suitable sensor version for each user, e.g., asensor optimized for higher throughput but with shorter lifetime oroptimized for longer lifetime but lower throughput.

Thus, issue tracking, complaint handling and customer care in generalcan be facilitated.

Modifications and variations of the disclosed embodiments are certainlypossible in light of the above description. It is therefore to beunderstood, that within the scope of the appended claims, theembodiments may be practiced otherwise than as specifically devised inthe above examples.

It is noted that terms like “preferably,” “commonly” and “typically” arenot utilized herein to limit the scope of the claimed subject matter orto imply that certain features are critical, essential, or evenimportant to the structure or function of the embodiments disclosedherein. Rather, these terms are merely intended to highlight alternativeor additional features that may or may not be utilized in a particularembodiment of the present disclosure.

For purposes of describing and defining the subject matter of thepresent disclosure it is noted that the terms “substantially” and“about” may be utilized herein to represent the inherent degree ofuncertainty that may be attributed to any quantitative comparison,value, measurement, or other representation. These terms are alsoutilized herein to represent the degree by which a quantitativerepresentation may vary from a stated reference without resulting in achange in the basic function of the subject matter at issue.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the embodiments describedherein without departing from the spirit and scope of the claimedsubject matter. Thus, it is intended that the specification cover themodifications and variations of the various embodiments describedherein, provided such modifications and variations come within the scopeof the appended claims and their equivalents.

What is claimed is:
 1. A method of determining an analyte concentrationin a sample by a sensor, the method comprising analyzing a sample signalfor an analyte being measured and if the sample signal is normal, thatis if it remains within an expected or predefined range and/or if itfollows an expected trend over a predefined measurement time, the methodcomprises comparing the sample signal with a first reference signal of areference solution measured prior to measuring the sample in order todetermine the analyte concentration, and if the sample signal isabnormal, that is if it falls at least in part out of the expected orpre-defined range and/or if it drifts beyond a predefined threshold overa predefined measurement time, the method comprises comparing the samplesignal with a calculated reference signal point obtained byinterpolation between the first reference signal and a second referencesignal of the same reference solution measured after measuring thesample.
 2. The method of claim 1, wherein the reference solution is astandby solution.
 3. The method of claim 1, wherein the first referencesignal is a last available measurement point of the first referencesignal or a projected point of the first reference signal.
 4. The methodof claim 1, wherein the second reference signal is a first availablemeasurement point of the second reference signal.
 5. The method of claim1, wherein the sample signal is a last available measurement point ofthe sample signal or a projected point of the sample signal.
 6. Themethod of claim 1, wherein the sample signal or reference signals arenormal if the normalized measurement points of the sample signal orreference signals respectively are of the same sign and wherein thesample signal or reference signals are abnormal if the normalizedmeasurement points of the sample signal or reference signalsrespectively have at least in part opposite sign.
 7. The method of claim1, wherein the sensor is an ion-selective electrode sensor and thesample signal is a potentiometric signal.
 8. The method of claim 1,wherein the analyte is a proton, chloride, sodium ion, potassium ion, orcalcium ion.
 9. The method of claim 1, wherein if the sample signal isrepeatedly abnormal for consecutive sample measurements, the methodcomprises indicating a sensor error.
 10. The method of claim 1, whereinthe sample is a QC sample and wherein if the sample signal, the firstreference signal and the second reference signal are normal and a QCfailure occurs, the method comprises repeating measurement of the QCsample and/or indicating an error other than a sensor error.
 11. Themethod of claim 10, wherein if any one or more of the sample signal, thefirst reference signal and the second reference signal are abnormal anda QC failure occurs a pre-defined number of times, the method comprisesindicating a sensor error.
 12. The method of claim 1, wherein the sampleis a calibrator and wherein if the sample signal, the first referencesignal and the second reference signal are normal and a calibrationfailure occurs, the method comprises repeating measurement of thecalibrator and/or indicating an error other than a sensor error.
 13. Themethod of claim 12, wherein if any one or more of the sample signal, thefirst reference signal and the second reference signal are abnormal anda calibration failure occurs a pre-defined number of times, the methodcomprises indicating a sensor error.
 14. The method of claim 1 furthercomprising saving any signal and/or any error in a database and/ortrouble shooting report of an analytical instrument.
 15. The method ofclaim 1 further comprising transmitting and collecting any signal and/orany error from one or more local analytical instruments to a remoteserver or cloud for monitoring instrument and/or sensor performance,and/or for analyzing data to improve instrument and/or sensorperformance and/or for facilitating service or trouble shooting and/orfor remotely triggering corrective actions or other types of actions.